1. Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis.
- Author
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Cooper-Knock J, Moll T, Ramesh T, Castelli L, Beer A, Robins H, Fox I, Niedermoser I, Van Damme P, Moisse M, Robberecht W, Hardiman O, Panades MP, Assialioui A, Mora JS, Basak AN, Morrison KE, Shaw CE, Al-Chalabi A, Landers JE, Wyles M, Heath PR, Higginbottom A, Walsh T, Kazoka M, McDermott CJ, Hautbergue GM, Kirby J, and Shaw PJ
- Subjects
- Amyotrophic Lateral Sclerosis diagnosis, Animals, Cell Line, Cell Survival, Exons, Female, Gene Knockdown Techniques, Glycosyltransferases metabolism, Golgi Apparatus enzymology, Humans, Male, Mice, Middle Aged, Neurons enzymology, Protein Domains genetics, Zebrafish embryology, Zebrafish Proteins genetics, Amyotrophic Lateral Sclerosis genetics, Glycosyltransferases genetics, Mutation
- Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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